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      siRNA Delivery Strategies: A Comprehensive Review of Recent Developments

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          Abstract

          siRNA is a promising therapeutic solution to address gene overexpression or mutations as a post-transcriptional gene regulation process for several pathological conditions such as viral infections, cancer, genetic disorders, and autoimmune disorders like arthritis. This therapeutic method is currently being actively pursued in cancer therapy because siRNA has been found to suppress the oncogenes and address mutations in tumor suppressor genes and elucidate the key molecules in cellular pathways in cancer. It is also effective in personalized gene therapy for several diseases due to its specificity, adaptability, and broad targeting capability. However, naked siRNA is unstable in the bloodstream and cannot efficiently cross cell membranes besides being immunogenic. Therefore, careful design of the delivery systems is essential to fully utilize the potential of this therapeutic solution. This review presents a comprehensive update on the challenges of siRNA delivery and the current strategies used to develop nanoparticulate delivery systems.

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          Mechanisms of gene silencing by double-stranded RNA.

          Gunter Meister, Thomas Tuschl (2004)
          Double-stranded RNA (dsRNA) is an important regulator of gene expression in many eukaryotes. It triggers different types of gene silencing that are collectively referred to as RNA silencing or RNA interference. A key step in known silencing pathways is the processing of dsRNAs into short RNA duplexes of characteristic size and structure. These short dsRNAs guide RNA silencing by specific and distinct mechanisms. Many components of the RNA silencing machinery still need to be identified and characterized, but a more complete understanding of the process is imminent.
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            Long-circulating and target-specific nanoparticles: theory to practice.

            S M Moghimi, A C Hunter, J C Murray (2001)
            The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.
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              The promises and pitfalls of RNA-interference-based therapeutics.

              Daniela Castanotto, John J Rossi (2009)
              The discovery that gene expression can be controlled by the Watson-Crick base-pairing of small RNAs with messenger RNAs containing complementary sequence - a process known as RNA interference - has markedly advanced our understanding of eukaryotic gene regulation and function. The ability of short RNA sequences to modulate gene expression has provided a powerful tool with which to study gene function and is set to revolutionize the treatment of disease. Remarkably, despite being just one decade from its discovery, the phenomenon is already being used therapeutically in human clinical trials, and biotechnology companies that focus on RNA-interference-based therapeutics are already publicly traded.
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                Author and article information

                Contributors
                Thomas Nann: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Nanomaterials (Basel)
                Journal ID (iso-abbrev): Nanomaterials (Basel)
                Journal ID (publisher-id): nanomaterials
                Title: Nanomaterials
                Publisher: MDPI
                ISSN (Electronic): 2079-4991
                Publication date (Electronic): 05 April 2017
                Publication date Collection: April 2017
                Volume: 7
                Issue: 4
                Electronic Location Identifier: 77
                Affiliations
                [1 ]Use-Inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA; katyayani.tatiparti@ 123456wayne.edu (K.T.); samaresh.sau@ 123456wayne.edu (S.S.); sushilkashaw@ 123456gmail.com (S.K.K.)
                [2 ]Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar 470003, India
                [3 ]Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI 48201, USA
                Author notes
                [* ]Correspondence: arun.iyer@ 123456wayne.edu ; Tel.: +1-313-577-5875
                Article
                Publisher ID: nanomaterials-07-00077
                DOI: 10.3390/nano7040077
                PMC ID: 5408169
                PubMed ID: 28379201
                SO-VID: 3afeddca-08a7-4f3f-84e0-e920fbf3f7b2
                Copyright © © 2017 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 04 January 2017
                Date accepted : 31 March 2017
                Categories
                Subject: Review

                Keywords: sirna,nanoparticles,delivery systems,cancer therapy,tumor,rnai,gene delivery,targeted delivery
                Data availability:
                Keywords: sirna, nanoparticles, delivery systems, cancer therapy, tumor, rnai, gene delivery, targeted delivery

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